Abstract
A new cyclic peptide, kakeromamide B (1), and previously described cytotoxic cyanobacterial natural products ulongamide A (2), lyngbyabellin A (3), 18E-lyngbyaloside C (4), and lyngbyaloside (5) were identified from an antimalarial extract of the Fijian marine cyanobacterium Moorea producens. Compound 1 exhibited moderate activity against Plasmodium falciparum blood-stages with an EC50 value of 8.9 µM whereas 2 and 3 were more potent with EC50 values of 0.99 µM and 1.5 nM, respectively. Compounds 1, 4, and 5 displayed moderate liver-stage antimalarial activity against P. berghei liver schizonts with EC50 values of 11, 7.1, and 4.5 µM, respectively. The threading-based computational method FINDSITEcomb2.0 predicted the binding of 1 and 2 to potentially druggable proteins of Plasmodium falciparum, prompting formulation of hypotheses about possible mechanisms of action. Kakeromamide B (1) was predicted to bind to several Plasmodium actin-like proteins and a sortilin protein suggesting possible interference with parasite invasion of host cells. When 1 was tested in a mammalian actin polymerization assay, it stimulated actin polymerization in a dose-dependent manner, suggesting that 1 does, in fact, interact with actin.
Highlights
Current malaria drugs are inadequate for future control of the disease due to the evolution of resistance by the malaria parasite, necessitating the discovery of medicines with novel mechanisms of action (MOA) [1,2]
Two sponge-derived antimalarial terpene isonitriles, diisocyanoadociane and axisonitrile-3, were predicted based on molecular dynamics simulations to interfere with heme detoxification, the same MOA as chloroquine [8]
Bioassay-guided fractionation using both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei pointed to four adjacent fractions that demonstrated potent blood and liver-stage antimalarial activity
Summary
Current malaria drugs are inadequate for future control of the disease due to the evolution of resistance by the malaria parasite, necessitating the discovery of medicines with novel mechanisms of action (MOA) [1,2]. Pharmaceutical options remain limited for the liver-stage of malaria infection. Natural products such as artemisinin discovered by Nobel-prize winner Tu Youyou have served as valuable sources of drugs to treat malaria [3,4]. Evolution of an efflux pump that prevents drug accumulation in the parasite’s food vacuole has resulted in resistance of Plasmodium to chloroquine [9], illustrating the need for discovery of natural products with unique molecular targets to support future disease management
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